Highly Potent Glucocorticoids

a glucocorticoid, high-potency technology, applied in the direction of steroid, organic chemistry, skeletal disorders, etc., can solve the problems of insensitivity, resistance to glucocorticoid therapy, and many adverse effects, so as to reduce unwanted side effects, reduce side effects, and reduce side effects.

Active Publication Date: 2016-09-01
VAN ANDEL RES INST +1
View PDF3 Cites 4 Cited by
  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0008]The evolution of glucocorticoids drugs was driven by the demand of lowering the unwanted side effects, while keeping the beneficial anti-inflammatory effects. Potency is a very important aspect of this evolution as many undesirable side effects are associated with high doses. The side effects can be minimized by highly potent glucocorticoids that achieve the same treatment effects at lower doses. This demand propelled the evolution of glucocorticoids from low to high potency. Cortisol is an endogenous glucocorticoid which has a relatively low potency while Mometasone Furoate (MF) is a highly potent synthetic glucocorticoid that has been used in treating many inflammation diseases. To understand the underlying mechanisms that drove the evolution of glucocorticoids, the inventors determined the X-ray structures of the glucocorticoid receptor (GR) ligand binding domain (LBD) bound to cortisol and MF. The cortisol-bound GR LBD revealed that the flexibility of the 1,2 single bond in the steroid A ring is primarily responsible for the low affinity of cortisol to GR. Meanwhile, the MF-bound GR LBD unveiled that the high potency of MF is achieved by its 17α furoate group, which completely fills the ligand binding pocket, thus providing additional anchor contacts for high affinity binding. A single amino acid in the ligand binding pocket, Q642, plays a discriminating role in ligand potency between MF and cortisol. Structure-based design led to synthesis of several novel glucocorticoids with much improved potency. Together these results reveal key structural mechanisms of glucocorticoid potency and provide a rational basis for developing highly potent glucocorticoids.

Problems solved by technology

However, the long-term use of glucocorticoids, especially at high doses, has many adverse consequences, including diabetes mellitus / glucose intolerance, hypertension, obesity, and osteoporosis (7, 8).
Finally, the development of insensitivity and resistance to glucocorticoid therapy is a major problem in treating common inflammatory diseases such as chronic obstructive pulmonary disease, rheumatoid arthritis and inflammatory bowel disease (19).

Method used

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
View more

Image

Smart Image Click on the blue labels to locate them in the text.
Viewing Examples
Smart Image
  • Highly Potent Glucocorticoids
  • Highly Potent Glucocorticoids
  • Highly Potent Glucocorticoids

Examples

Experimental program
Comparison scheme
Effect test

example 1

Overall Structure of the Cortisol- and MF-Bound GR LBDs

[0196]Crystallization of the GR LBD has always been a challenge due to its solubility problem. The original GR LBD structure was determined with a high affinity ligand DEX (27), bound to the GR LBD with F602S mutation, which improve protein solubility. However, cortisol is a much weaker ligand than DEX and the F602S mutation is not sufficient for stabilizing the GR LBD bound to cortisol, an endogenous hormone (FIG. 8, lane 1). To identify amino acids that might increase GR LBD solubility without affecting overall structure, we aligned GR with the closest members of steroid hormone family, MR, androgen receptor (AR) and progesterone receptor (PR), which are much more soluble than GR. Besides F602, residue C622, T668, S674 and V675 distinguish from the conserved sequences of the family, so the inventors mutated those amino acids back to the conserved residues (F602A, C622Y, T668V, S674T and V675I, termed AYVTI). Most of these resi...

example 2

Potency, Affinity of Cortisol, DEX and MF

[0198]The change of chemical structures (FIG. 2A) of cortisol, DEX and MF silhouettes the evolution of glucocorticoid: from simple to complex and from one level to multiple levels. The cortisol structure provides a basic 4 ring steroid backbone; then DEX adds 1,2 double bone, 16 methylation and 9α halogenation (FIG. 2A); and MF further chloridizes at 22, and more importantly, adds a lipophilic furoate ester group at 17α (FIG. 2A), replacing the hydroxyl group of DEX and cortisol. To test the effects of those chemical changes on GR potency, the inventors side by side compared MF, DEX, and cortisol activities on both GR transactivation and transrepression in the format of full dose-response curve. For transactivation, the inventors used an MMTV-driven luciferase reporter system (FIG. 2B). MF and DEX showed almost the same efficacy (maximal activity) at the saturation concentration (1 μM), whereas cortisol at its saturation concentration (10 μM)...

example 3

The Flexibility of 1,2 Single Bond Attributed to the Low Affinity of Cortisol to GR

[0201]To understand the underlying mechanism of the low affinity of cortisol, the inventors did a structural comparison of cortisol-bound GR LBD and DEX-bound GR LBD. The overall structure of cortisol-bound GR LBD is almost exactly same as DEX-bound GR LBD, there is no notable conformation change. Then the inventors looked into the detail of ligand binding. As mentioned above, DEX differentiate from cortisol only via: 1,2 double bond, 9α halogenation and 16 methylation (FIG. 2A). The C1-C2 double bond of DEX causes the steroid A ring and the C3-ketone group to become planar, thus allowing the C3-ketone to readily interact with R611 and Q570 (FIG. 3A). In contrast, because of the flexibility of the cortisol C1-C2 single bond, the steroid A ring needs to bend to form a hydrogen bond with R611 and Q570. Also, since the C1-C2 single bond of unbound cortisol oscillates between two conformations (above and ...

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to view more

PUM

PropertyMeasurementUnit
temperatureaaaaaaaaaa
pressureaaaaaaaaaa
temperatureaaaaaaaaaa
Login to view more

Abstract

The present invention relates to novel glucocorticoid compounds. The invention also relates to methods of using these compounds, the synthesis of these compounds, and to compositions and formulations comprising the glucocorticoid compounds, and uses thereof.

Description

CROSS REFERENCE TO RELATED APPLICATION[0001]This PCT application claims the benefit of U.S. provisional application Ser. No. 61 / 882,444, filed on Sep. 25, 2013. The entire contents of this document are hereby incorporated by reference.FEDERAL FUNDING[0002]This invention was made with government support under DK066202 and DK071662 awarded by the National Institute of Diabetes and Digestive and Kidney Diseases / National Institutes of Health. The government has certain rights in the invention.TECHNICAL FIELD OF THE INVENTION[0003]The present invention relates to novel glucocorticoid compounds. The invention also relates to methods of using these compounds, the synthesis of these compounds, and to compositions and formulations comprising the glucocorticoid compounds, and uses thereof.BACKGROUND OF THE INVENTION[0004]Glucocorticoids such as prednisone, Dexamethasone (DEX), and budesonide are the most effective anti-inflammatory drugs. They are widely used to treat inflammation and autoimm...

Claims

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to view more

Application Information

Patent Timeline
no application Login to view more
Patent Type & Authority Applications(United States)
IPC IPC(8): C07J71/00
CPCC07J71/0047C07J3/005C07J5/0053A61P1/04A61P11/06A61P13/12A61P17/02A61P17/10A61P19/02A61P29/00A61P37/02A61P43/00A61P5/44
Inventor XU, HUAQIANG ERICHE, YUANZHENGMELCHER, KARSTENYI, WEISHI, JINGLING
Owner VAN ANDEL RES INST
Who we serve
  • R&D Engineer
  • R&D Manager
  • IP Professional
Why Eureka
  • Industry Leading Data Capabilities
  • Powerful AI technology
  • Patent DNA Extraction
Social media
Try Eureka
PatSnap group products

Browse by: Latest US Patents, China's latest patents, Technical Efficacy Thesaurus, Application Domain, Technology Topic.

© 2024 PatSnap. All rights reserved.Legal|Privacy policy|Modern Slavery Act Transparency Statement|Sitemap